Podcast with Jim Stephenson Jr. on vitamin/hormone D

[Dave Clark]

Jim Stephenson Jr. on vitamin D, for those interested in hearing an alternative view on supplementation, etc.


View: https://www.youtube.com/watch?v=t2_nmxtVeG4

 

[md_a]

Vitamin D Deficiency and Its Association with Thyroid Disease​

Objectives​

Vitamin D deficiency is a global health problem, its role as an immune modulator has been recently emphasized. The evidence is increasingly pointing towards vitamin D significant role in reducing the incidence of autoimmune diseases. However, at this time the research on its role in autoimmune and thyroid disease is not conclusive.
We aimed to examine the relationship between hypothyroidism and vitamin D deficiency and to clarify the relation between serum calcium levels with hypothyroid disease.

Subjects and Methods​

Serum vitamin D (25-OH) levels were measured in 30 patients with hypothyroidism and 30 healthy subjects, utilizing the spectrophotometric method. Vitamin D deficiency was designated at levels lower than 20 ng/ml. Thyroid hormones (TSH, T3 and T4) and calcium levels were evaluated in all participants.

Results​

Serum 25(OH) vit D was significantly lower in hypothyroid patients than in controls (t=−11.128, P =0.000). Its level was insignificantly decreased in females than male patients (t=− 1.32, P >0.05). Moreover, serum calcium levels recorded a significant decrease in hypothyroid patients when compared to controls (t= −5.69, P = 0.000).

Conclusion​

Our results indicated that patients with hypothyroidism suffered from hypovitaminosis D with hypocalcaemia that is significantly associated with the degree and severity of the hypothyroidism. That encourages the advisability of vit D supplementation and recommends the screening for Vitamin D deficiency and serum calcium levels for all hypothyroid patients.

Vitamin D Deficiency and Its Association with Thyroid Disease

Vitamin D deficiency is a global health problem, its role as an immune modulator has been recently emphasized. The evidence is increasingly pointing towards vitamin D significant role in reducing the incidence of autoimmune diseases. However, at this ...

www.ncbi.nlm.nih.gov

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Mobilising vitamin D from adipose tissue: The potential impact of exercise​

Abstract​

Vitamin D is lipophilic and accumulates substantially in adipose tissue. Even without supplementation, the amount of vitamin D in the adipose of a typical adult is equivalent to several months of the daily reference nutrient intake (RNI). Paradoxically, despite the large amounts of vitamin D located in adipose tissue, individuals with obesity are often vitamin D deficient according to consensus measures of vitamin D status (serum 25‐hydroxyvitamin D concentrations). Thus, it appears that vitamin D can become ‘trapped’ in adipose tissue, potentially due to insufficient lipolytic stimulation and/or due to tissue dysfunction/adaptation resulting from adipose expansion. Emerging evidence suggests that exercise may mobilise vitamin D from adipose (even in the absence of weight loss). If exercise helps to mobilise vitamin D from adipose tissue, then this could have important ramifications for practitioners and policymakers regarding the management of low circulating levels of vitamin D, as well as chronically low levels of physical activity, obesity and associated health conditions. This perspective led us to design a study to examine the impact of exercise on vitamin D status, vitamin D turnover and adipose tissue vitamin D content (the VitaDEx project). The VitaDEx project will determine whether increasing physical activity (via exercise) represents a potentially useful strategy to mobilise vitamin D from adipose tissue.

Conclusions​

Vitamin D can accumulate in large amounts in adipose tissue where it may become sequestered. Preliminary evidence indicates that exercise may be a potential strategy to mobilise vitamin D from adipose tissue. We will examine this concept in a new research study (the VitaDEx project). This research will help us to understand the impact of exercise on vitamin D status and whether increasing physical activity represents a potentially useful strategy to mobilise vitamin D from adipose tissue. If exercise helps to mobilise vitamin D from adipose, then this could have important ramifications for practitioners and policymakers regarding the management of (i) low vitamin D status, (ii) obesity and associated conditions and (iii) low levels of physical activity. Current public health strategies typically approach vitamin D deficiency by increasing intake and/or synthesis of vitamin D (e.g. dietary supplementation or UV treatment). Notably, overweight/obesity reduces the impact of dietary supplementation with vitamin D on 25(OH)D concentrations (Arunabh et al. 2003; Snijder et al. 2005; Blum et al. 2008a; Beydoun et al. 2010) and the systemic 25(OH)D response to UV irradiation is significantly impaired (Wortsman et al. 2000). Thus, complementing conventional intake/synthesis strategies with techniques to mobilise endogenous vitamin D has the capacity to mutually enhance the overall effectiveness of interventions to improve vitamin D status.

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"The aging suppressing gene discovered in 1997, named after the Greek life-promoting goddess Klotho, suppresses the reabsorption of phosphate by the kidney (which is also a function of the parathyroid hormone), and inhibits the formation of the activated form of vitamin D, opposing the effect of the parathyroid hormone. In the absence of the gene, serum phosphate is high, and the animal ages and dies prematurely. In humans, in recent years a very close association has been has been documented between increased phosphate levels, within the normal range, and increased risk of cardiovascular disease. Serum phosphate is increased in people with osteoporosis (Gallagher, et al., 1980), and various treatments that lower serum phosphate improve bone mineralization, with the retention of calcium phosphate (Ma and Fu, 2010; Batista, et al., 2010; Kelly, et al., 1967; Parfitt, 1965; Kim, et al., 2003)."RP

The Klotho gene and its related protein were identified as a putative aging factors in 1997, when the aging process was aggravated in a group of Klotho knockout mice (1). Klotho is expressed mainly in the kidneys, parathyroid glands, brain choroid plexus, and testes (2-4). Studies have confirmed Klotho expression in other tissues, including the aorta, colon, thyroid gland, and pancreas, but the kidney remains the strongest Klotho-producing organ (5).

There are two types of Klotho: circulating and membrane-bound. The latter functions as a co-receptor for fibroblast growth factor-23 (FGF23). The membrane-bound form, after losing its membrane domain, enters into the circulation as soluble Klotho (sKl), acting as a hormone with anti-aging and anti-oxidative stress properties; sKl can also be directly generated by alterative splicing of the Klotho transcript (2, 5). Klotho deficiency is an early biomarker for chronic kidney disease, and its upregulation could protect the kidney from fibrosis progression (6). The beneficial effect of physical activity in preventing premature mortality has been established by epidemiological studies showing that exercise may delay aging through various mechanisms. Exercise-induced Klotho upregulation could be one explanation. Klotho upregulates nitrous oxide (NO) production and inhibits angiotensin II-induced reactive oxygen species production within endothelial cells (7). In an epidemiological study, handgrip strength, an indicator of total body muscle strength, was correlated with plasma Klotho concentration (8).

Klotho production is affected by many physiological and non-physiological conditions. Angiotensin II downregulates renal Klotho protein expression (23), and AT1R blockade increases circulating Klotho. Conversely, oxidative stress downregulates Klotho production (23).
Serum Klotho Levels in Trained Athletes
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In chronic infectious diseases, low 25(OH)D is often found with elevated levels of the more active metabolite 1,25 dihydroxyvitamin D (1,25D).
1,25 (OH)2D is influenced by PTH and chronic infections, pathogens and aging.
The classic symptoms of vitamin D toxicity are entirely attributable to hypercalcemia. High 1,25 (OH)2D predispose to hypercalcemia.
Macrophages within the granuloma ↑ calcitriol (1,25-[OH]2 vitamin D3) activation → hypercalcemia
Granulomatous disorders (e.g., sarcoidosis): due to increased 1α-hydroxylase activation in epithelioid macrophages → increased 1,25-dihydroxyvitamin D synthesis
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The majority of hypercalcemia cases in sarcoidosis are explained by the overproduction of 1,25(OH)2D3 (calcitriol) by activated macrophages. Despite quite convincing evidence supporting this hypothesis, some questions have yet to be completely answered. Moreover, some recent studies suggest that vitamin D supplementation may improve not only calcium homeostasis but also the course of sarcoidosis.
Conclusions
Sarcoidosis-associated hypercalcemia is quite a common problem as it affects about 6% of patients. It is also one of the indications to introduce pharmacotherapy with steroids. Its pathophysiology appears to be quite well explained. Although it seems logical that vitamin D metabolites should be good tools for assessing disease activity, clinically it is not that simple. Increased conversion of 25(OH)D3 to calcitriol suggests that perhaps the ratio of 25(OH)D3 to 1,25(OH)2D3 could be more adequate than absolute values. One study confirms this theory.
SAGE Journals: Your gateway to world-class research journals
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In granulomatous disease hypercalcemia is produced because of the presence of 1α-hydroxylase enzyme in macrophages (6) and giant cells that form part of the granuloma. In the granuloma the 25 (OH) vitamin D is converted to 1,25-(OH)2 vitamin D without any type of homeostatic control.
Hypercalcemia secondary to granulomatous disease caused by the injection of methacrylate: a case series
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Three types of the Klotho protein are distinguished, i.e., cell membrane-related, intracellular, and secretory forms. Klotho associated with the cell membrane (transmembrane Klotho) can be detected in the kidneys, pituitary gland, inner ear, brain, parathyroid glands, pancreas, large intestine, skeletal muscles, bladder, ovaries, testes, and epithelial breast cells [12]. The largest concentrations are detected in distal convoluted tubules, in the kidney, and in choroid plexus of the brain [1]. Klotho is involved in the renal metabolism of calcium, phosphates, and vitamin D. The membrane Klotho forms a complex with the fibroblast growth factor receptor (FGFR) and provides selective binding affinity to the fibroblast growth factor (FGF) [13]. This complex inhibits phosphate resorption in the proximal tubule of the kidney. In the distal tubule, it also regulates Ca2+ absorption by stabilizing the Ca2+ transient receptor potential vanilloid 5 (TRPV5) channel in the plasma membrane. It inhibits renal 1-alpha 25 hydroxylase activity, thus decreasing the levels of circulating calcitriol. Therefore, hyperphosphatemia, hypercalcemia, elevated plasma calcitriol, vascular calcification, and premature aging can be observed in Klotho-deficient mice [14]. FGF23 leads to the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), which activates serum and glucocorticoid-induced kinase 1 (SGK1) in cortical renal tubular cells. SGK1 activates with-no-lysine kinase 4 (WNK 4), stimulating WNK4-TRPV5 complex formation [15].

Klotho has been shown to inhibit 1-α hydroxylase, an enzyme responsible for the production of 1,25-dihydroxyvitamin D3, which is an active form of vitamin D [16]. Lower levels of Klotho in mice induced the formation and toxicity of vitamin D. The toxicity was reduced by limiting the formation of vitamin D [17].

On the molecular level, permanent chronic inflammation, cell proliferation disorders, or cellular aging leads to the formation of a number of age-related chronic diseases, such as obesity, diabetes, atherosclerosis, Alzheimer’s disease (AD), cancer, renal diseases, or degenerative diseases [18]. The secretory Klotho results in the reduction in TNFα and IFNγ, which can show anti-inflammatory properties. The Wnt protein is a signaling molecule that regulates intercellular interactions in the developmental period and in adult tissues. Increased signaling (activity) of Wnt disrupts the function of stem and progenitor cells and leads to cellular aging. Liu et al. [19] demonstrated that Klotho can interact with Wnt, which results in the inhibition of Wnt pathway activity, thus inhibiting the aging process. Cellular aging is also activated by oxidative stress and mitochondrial dysfunction by stimulating the p53/p21 pathways. The p53 protein is a tumor suppressor and can be activated by the ataxia telangiectasia-mutated kinase that, in turn, activates p21, which effectively inhibits cell proliferation [20]. Klotho deficiency results in the overexpression of p53/p21 by inhibiting the formation of new cells and increasing the number of aging cells [21]. Therefore, Klotho supplementation reduces cellular aging by inhibiting the p53/p21 signaling pathway [22].
Klotho protein in neurodegenerative disorders

 

[ddjd]

Jim Stephenson Jr. on vitamin D, for those interested in hearing an alternative view on supplementation, etc.


View: https://www.youtube.com/watch?v=t2_nmxtVeG4

View: https://youtu.be/AMv0tB_luQ0



View: https://youtu.be/d66ZRyvrQEI